Clear Cell Renal CarcinomaPhase 1/2NCT02348008
Phase Ib and Phase II Studies of MK-3475 in Combination + for Renal Cell Carcinoma:
A Phase 1/2 study testing MK-3475 and Bevacizumab in people with Clear Cell Renal Carcinoma, run by Arkadiusz Z. Dudek, MD at 9 sites in United States.
Trial summary
This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Clear Cell Renal Carcinoma
- What is being tested?
- MK-3475 and Bevacizumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 61 participants
- Where
- 9 sitesUnited States
- Study dates
- Mar 2015to 5 Dec 2019
- Phase
- Phase 1/2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Male or female ≥ 18 years of age at time of consent.
- Phase Ib dose escalation cohort study: subjects with histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) after failure of at least one systemic therapy for metastatic disease (including, but not limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not required.
- Phase II study: subjects with treatment-naïve histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) and who are candidates for standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not required.
- Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and obtained by imaging within 28 days prior to registration for protocol therapy.
- Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol therapy.
- Life expectancy of 6 months or greater as determined by the treating physician.
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- Adequate hepatic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:
- total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 x ULN
- and aspartate aminotransferase (AST) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
- and alanine aminotransferase (ALT) ≤ 2.5 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
- Adequate renal function within 28 days prior to registration for protocol therapy defined by either of the following criteria:
- serum creatinine ≤ 3 mg/dL
- OR if serum creatinine > 3 mg/dL, estimated glomerular filtration rate (GFR) ≥ 20 mL/min
- Adequate hematologic function within 28 days prior to registration for protocol therapy defined as meeting all of the following criteria:
- hemoglobin ≥ 9 g/dL
- and absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L
- and platelet count ≥ 100 × 10^9/L
- Adequate coagulation functioning within 28 days prior to registration for protocol therapy defined by either of the following criteria:
- INR < 1.5 × ULN
- OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.
- Provided written informed consent and HIPAA authorization for release of personal health information, approved by an Institutional Review Board/Independent Ethics Committee (IRB/IEC).
- Women of childbearing potential (WOCP) must not be pregnant or breast-feeding. A negative serum or urine pregnancy test is required within 72 hours of study registration. If the urine test cannot be confirmed as negative, a serum pregnancy test will be required.
- Women of childbearing potential (WOCP) must be willing to use two effective methods of birth control such as an oral, implantable, injectable, or transdermal hormonal contraceptive, an intrauterine device (IUD), use of a double barrier method (condoms, sponge, diaphragm, or vaginal ring with spermicidal jellies or cream), or total abstinence for the course of the study until 120 days after the last dose of study drug.
- Men who are not surgically sterile (vasectomy) must agree to use an acceptable method of contraception. Male subjects with female sexual partners who are pregnant, possibly pregnant, or who could become pregnant during the study must agree to use condoms from the first dose of study drug through at least 120 days after the last dose of study drug. Total abstinence for the same study period is an acceptable alternative.
- Availability of tissue if applicable (from the primary tumor or metastases) for correlative studies.
- Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests, and other study procedures.
Who cannot join
- Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4 weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events of such agents administered more than 4 weeks earlier.
- Phase II: has had prior therapy for metastatic renal cell carcinoma.
- Surgery within 4 weeks prior to study treatment except for minor procedures: NOTES: Hepatic biliary stent placement is allowed. Subject must have adequately recovered from the toxicity and/or complications of major surgery prior to study registration, as determined by the treating physician.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
- Previously received an organ or allogeneic progenitor/stem cell transplant.
- Received a live vaccine within 30 days prior to the first dose of trial treatment: Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
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- History of blood clots, pulmonary embolism, or deep vein thrombosis unless controlled by anticoagulant treatment.
- Known history of human immunodeficiency virus [(HIV) HIV 1/2 antibodies].
- Known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
- Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to study registration.
- Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs).
- NOTE: Replacement therapy (eg., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
- Received prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events from previously administered agents. NOTE: Subjects with ≤ Grade 2 neuropathy are an exception to this criterion and can still be considered for the study.
- Any clinically significant infection defined as any acute viral, bacterial, or fungal infection that requires specific treatment. NOTE: Anti-infective treatment must be completed ≥ 7 days prior to study registration.
- Evidence of interstitial lung disease, history of (non-infectious) pneumonitis that required steroids, or current pneumonitis.
- Known history of active tuberculosis.
- Any other severe, uncontrolled medical condition, including uncontrolled diabetes mellitus or unstable congestive heart failure.
- Known allergy to pembrolizumab or any of its excipients.
- Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies.
- Any condition that, in the opinion of the treating physician, would exclude the subject from receiving bevacizumab. Examples may include but are not limited to:
- Hemoptysis (defined as > ½ teaspoon of blood)
- Pre-existing bleeding diathesis, coagulopathy or hemorrhage
- Myocardial infarction or cerebrovascular accident within 6 months prior to study registration
- Any drugs or supplements that interfere with blood clotting can raise the risk of bleeding during treatment with bevacizumab. These drugs include vitamin E, non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, ibuprofen (Advil, Motrin), and naproxen (Aleve, Naprosyn), warfarin (Coumadin), ticlopidine (Ticlid), and clopidogrel (Plavix).These agents should be used with caution.
- Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for enrollment in this study.
- Presence of any non-healing wound, fracture, or ulcer within 28 days prior to study registration.
- Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.
- Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.
- No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, Gleason ≤ grade 7 prostate cancers, or other cancer for which the subject has been disease-free for at least 5 years.
- Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
- Treatment with any investigational agent within 28 days prior to registration for protocol therapy and the subject must have recovered from the acute toxic effects of the regimen.
Trial locations and contacts
9 sites in 1 country.
9 sites in 1 country
United States9 sites
University of Michigan Comprehensive Cancer Center
Ann Arbor, Michigan, 48109
Northwestern University, Robert H. Lurie Cancer Center
Chicago, Illinois, 60611
University of Illinois Cancer Center
Chicago, Illinois, 60612
Penn State Hershey Cancer Institute
Hershey, Pennsylvania, 17033
University of Iowa, Holden Comprehensive Cancer Center
Iowa City, Iowa, 52242
Michigan State University, Breslin Cancer Center
Lansing, Michigan, 48910
University of Minnesota: Masonic Cancer Center
Minneapolis, Minnesota, 55455
Rutgers Cancer Institute of New Jersey
New Brunswick, New Jersey, 08903
University of Nebraska, Fred and Pamela Buffet Cancer Center
Omaha, Nebraska, 68198
About this study
Official title: Phase Ib and Phase II Studies of Anti-PD-1 Antibody MK-3475 in Combination With Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer Research Consortium GU14-003
This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.
Read the detailed description
OUTLINE: This is a multi-center study.
The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.
PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:
Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.
PHASE II INVESTIGATIONAL TREATMENT:
The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.
Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.
Life Expectancy: 6 months or greater
The following baseline labs must be completed within 28 days prior to registration for protocol therapy:
Hematopoietic:
- Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
- Platelets ≥ 100 × 10 9/L
- Hemoglobin (Hgb) ≥ 9.0 g/dL
Renal:
- Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
- OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min
Hepatic:
- Total serum bilirubin ≤ 1.5 × ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
- OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy
Coagulation:
- INR < 1.5 × ULN
- OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.
- Conditions
- Clear Cell Renal Carcinoma
- Being tested
- MK-3475, Bevacizumab
- Keywords
- MK-3475, Pembrolizumab, Bevacizumab
- Medical subject headings
- Carcinoma, Renal Cell
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
MK-3475Drug
Also called Pembrolizumab
Arm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV
BevacizumabDrug
Also called Avastin
Arm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV
MK-3475Drug
Also called Pembrolizumab
Arm B: Phase II Treatment: 200mg IV
BevacizumabDrug
Also called Avastin
Arm B: Phase II Treatment: administered at the maximum safe dose of 10mg or 15mg as established in the Phase 1b dose escalation cohort study.
| Study group | Role | What they receive |
|---|---|---|
| Arm A - Phase 1b Dose Escalation Cohort | Experimental | Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. Receives: Drug: MK-3475; Drug: Bevacizumab |
| Arm B - Phase II Investigational Treatment | Other | The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Receives: Drug: MK-3475; Drug: Bevacizumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Phase 1b: Maximum Safe Dose of Treatment Regimen
To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.
Measured: Every 21 days while on treatment (estimated 4 months)
Overall Response Rate
To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where:
Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Measured: Every 6 weeks while on treatment (estimated 10 months)
Secondary outcomes (4)
Progression-Free Survival
To determine median progression-free survival (PFS) for this patient population, per RECIST 1.1 where:
Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Measured: Up to two years from enrollment
Overall Survival
To determine if treatment regimen improves overall survival for this patient population. Median overall survival will be calculated up to 2 years from registration.
Measured: Up to 2 years from registration
Clinical Benefit Rate
To determine the proportion of subjects with clinical benefit (complete response, partial response, or stable disease) based on RECIST 1.1, where:
Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
Measured: Every 6 months while on treatment (estimated 4-10 months)
Characterize Adverse Events
Characterize adverse effects (AE) of pembrolizumab in combination with bevacizumab in subjects with metastatic RCC after failure of at least one systemic therapy. Toxicity will be assessed using CTCAE version 4. All grade 3 and 4 treatment-related adverse events will be reported.
Measured: Every week while on treatment (estimated 4-10 months)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted28 Jan 2015 (estimated)
- Study startMar 2015
- Primary completion5 Dec 2019
- Study completion5 Dec 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Clear Cell Renal CarcinomaStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1/2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 61 participants (actual)
Sponsor and investigators
- Lead sponsor
- Arkadiusz Z. Dudek, MD
- Sponsor type
- University, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Big Ten Cancer Research Consortium
- Responsible party
- Sponsor-investigator, Arkadiusz Z. Dudek, MD, Big Ten Cancer Research Consortium
- Investigators
- Arkadiusz Z Dudek, M.D., Ph.D., Study chair, Big Ten Cancer Research Consortium
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02348008
- Sponsor's protocol ID
- BTCRC GU14-003
- Status last verified
- Aug 2022
- First submitted
- 16 Jan 2015
- Last updated
- 14 Sep 2022
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- Individual data sharing
- No
Publications
Dudek AZ, Liu LC, Gupta S, Logan TF, Singer EA, Joshi M, Zakharia YN, Lang JM, Schwarz JK, Al-Janadi A, Alva AS. Phase Ib/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003. J Clin Oncol. 2020 Apr 10;38(11):1138-1145. doi: 10.1200/JCO.19.02394. Epub 2020 Feb 25.
PubMed 32097091
Study at a glance
From the registry record, last updated by the sponsor on 14 Sep 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase Ib and Phase II Studies of Anti-PD-1 Antibody MK-3475 in Combination With Bevacizumab for the Treatment of Metastatic Renal Cell Carcinoma: Big Ten Cancer Research Consortium GU14-003
- ClinicalTrials.gov ID
- NCT02348008
- Acronym / sponsor ID
- BTCRC GU14-003
- Conditions
- Clear Cell Renal Carcinoma
- Keywords
- MK-3475, Pembrolizumab, Bevacizumab
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 61 participants (actual)
- Lead sponsor
- Arkadiusz Z. Dudek, MDUniversity, hospital or other
- Collaborators
- Merck Sharp & Dohme LLC, Big Ten Cancer Research Consortium
- Study start
- Mar 2015 (actual)
- Primary completion
- 5 Dec 2019 (actual)
- Study completion
- 5 Dec 2019 (actual)
- First posted
- 28 Jan 2015 (estimated)
- Results
- Posted 31 Jul 2020
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is an open label, multi-institutional, single arm study of dose escalation phase Ib cohort, followed by a phase II cohort of anti-PD-1 antibody MK-3475 in combination with bevacizumab. No randomization or blinding is involved.
Detailed description
OUTLINE: This is a multi-center study.
The phase Ib dose escalation study will evaluate MK-3475 in combination with bevacizumab in subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease. The phase II trial will determine the activity of the combination of MK-3475 and bevacizumab in first line therapy for subjects with metastatic clear cell renal carcinoma.
PHASE Ib DOSE ESCALATION INVESTIGATIONAL TREATMENT:
Cohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions.
If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2.
PHASE II INVESTIGATIONAL TREATMENT:
The maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. Treatment will continue until disease progression, unacceptable toxicity, subject refusal, or subject death either from progression of disease, the therapy itself, or from other causes. Subjects who voluntarily stop the study, have progressive disease, or unacceptable toxicities will be followed for a total of 24 months.
Karnofsky Performance Status (KPS) ≥ 70% within 28 days prior to registration for protocol therapy.
Life Expectancy: 6 months or greater
The following baseline labs must be completed within 28 days prior to registration for protocol therapy:
Hematopoietic:
- Absolute neutrophil count (ANC) ≥ 1.5 × 10 9/L
- Platelets ≥ 100 × 10 9/L
- Hemoglobin (Hgb) ≥ 9.0 g/dL
Renal:
- Serum creatinine ≤ 1.5 × upper limit of normal (ULN)
- OR, if serum creatinine > 1.5 × ULN, estimated glomerular filtration rate (eGFR) ≥ 40 mL/min
Hepatic:
- Total serum bilirubin ≤ 1.5 × ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN
- OR, AST and ALT ≤ 5 × ULN if liver function abnormalities are due to underlying malignancy
Coagulation:
- INR < 1.5 × ULN
- OR for subjects receiving warfarin or LMWH, the subjects must, in the investigator's opinion, be clinically stable with no evidence of active bleeding while receiving anticoagulant therapy. The INR for these subjects may exceed 1.5 × ULN if that is the goal of anticoagulant therapy.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Arm A - Phase 1b Dose Escalation Cohort | Experimental | Drug: MK-3475, Drug: BevacizumabCohort 1 will consist of 3-6 patients who will receive MK-3475 200mg and bevacizumab 10mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. Cohort 2 will consist of 3-9 patients who will receive MK-3475 200mg and bevacizumab 15mg on day 1 of the 21-day cycle. The drugs are administered 15-30 minutes apart in separate intravenous infusions. If none of the 3 subjects experience a dose limiting toxicity (DLT) during the first cycle of therapy, an additional 3 subjects will be enrolled at dose level 2. If all three subjects in dose level 2 complete the first cycle of therapy without DLT, 3 more subjects will be enrolled to ensure only 0-1 of 6 subjects have a DLT. There will be no further escalation beyond dose level 2. |
| Arm B - Phase II Investigational Treatment | Other | Drug: MK-3475, Drug: BevacizumabThe maximum safe dose of MK-3475 in combination bevacizumab (as determined in the phase 1b cohort) will be given on day 1 of each 21 day cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (26 listed)
- Male or female ≥ 18 years of age at time of consent.
- Phase Ib dose escalation cohort study: subjects with histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) after failure of at least one systemic therapy for metastatic disease (including, but not limited to prior therapy with interleukin 2, interferon, bevacizumab, VEGF TKI, and mTOR) for metastatic disease. NOTE: A biopsy to prove metastatic disease is not required.
- Phase II study: subjects with treatment-naïve histologically assessed metastatic clear cell RCC (defined as more than 50% clear cell component) and who are candidates for standard first-line therapy. NOTE: A biopsy to prove metastatic disease is not required.
- Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to RECIST 1.1, and obtained by imaging within 28 days prior to registration for protocol therapy.
- Karnofsky Performance Status ≥ 70% within 28 days prior to registration for protocol therapy.
Key exclusion criteria (31 listed)
- Phase Ib: Received prior monoclonal antibody therapy other than bevacizumab within 4 weeks of study registration or who has not recovered (i.e., ≤ Grade 1 or at baseline) from adverse events of such agents administered more than 4 weeks earlier.
- Phase II: has had prior therapy for metastatic renal cell carcinoma.
- Surgery within 4 weeks prior to study treatment except for minor procedures: NOTES: Hepatic biliary stent placement is allowed. Subject must have adequately recovered from the toxicity and/or complications of major surgery prior to study registration, as determined by the treating physician.
- Known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
- Previously received an organ or allogeneic progenitor/stem cell transplant.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| MK-3475Also: PembrolizumabArm A: Phase 1b Cohort 1: 200mg IV; Arm A: Phase 1b Cohort 2: 200mg IV | Drug | Arm A - Phase 1b Dose Escalation Cohort |
| BevacizumabAlso: AvastinArm A: Phase 1b Cohort 1: 10mg IV; Arm A: Phase 1b Cohort 2: 15mg IV | Drug | Arm A - Phase 1b Dose Escalation Cohort |
| MK-3475Also: PembrolizumabArm B: Phase II Treatment: 200mg IV | Drug | Arm B - Phase II Investigational Treatment |
| BevacizumabAlso: AvastinArm B: Phase II Treatment: administered at the maximum safe dose of 10mg or 15mg as established in the Phase 1b dose escalation cohort study. | Drug | Arm B - Phase II Investigational Treatment |
Primary outcome
Phase 1b: Maximum Safe Dose of Treatment Regimen
Time frame: Every 21 days while on treatment (estimated 4 months)
To establish the maximum tested safe dose of bevacizumab in combination with 200mg of MK-3475(pembrolizumab) for subjects with metastatic clear cell renal carcinoma after failure of at least one systemic therapy for metastatic disease.
Overall Response Rate
Time frame: Every 6 weeks while on treatment (estimated 10 months)
To determine the activity of combination of MK-3475 and bevacizumab in first line therapy for subjects with treatment naïve metastatic clear cell RCC as assessed by response rates (complete or partial response) By calculating the proportion of subjects with a response (CR, PR) based on RECIST 1.1 where: Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the LD of target lesions, taking as reference the baseline sum LD Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started
4 secondary outcomes
Progression-Free Survival
Time frame: Up to two years from enrollment
Overall Survival
Time frame: Up to 2 years from registration
Clinical Benefit Rate
Time frame: Every 6 months while on treatment (estimated 4-10 months)
Characterize Adverse Events
Time frame: Every week while on treatment (estimated 4-10 months)
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 14 Sep 2022.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Derived from this study: PubMed 32097091Dudek AZ, Liu LC, Gupta S, Logan TF, Singer EA, Joshi M, Zakharia YN, Lang JM, Schwarz JK, Al-Janadi A, Alva AS. Phase Ib/II Clinical Trial of Pembrolizumab With Bevacizumab for Metastatic Renal Cell Carcinoma: BTCRC-GU14-003. J Clin Oncol. 2020 Apr 10;38(11):1138-1145. doi: 10.1200/JCO.19.02394. Epub 2020 Feb 25.
- Big Ten Cancer Research Consortium WebsiteLink provided by the sponsor.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Arkadiusz Z Dudek, M.D., Ph.D. study chair
Big Ten Cancer Research Consortium
9 sites in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1/2 study testing MK-3475 and Bevacizumab in people with Clear Cell Renal Carcinoma, run by Arkadiusz Z. Dudek, MD at 9 sites in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 26 inclusion and 31 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 14 Sep 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 9 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this combined phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 31 Jul 2020). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Phase 1b: Maximum Safe Dose of Treatment Regimen (time frame: Every 21 days while on treatment (estimated 4 months)). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02348008, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 14 Sep 2022.